The selective activation of p53 target genes regulated by SMYD2 in BIX-01294 induced autophagy-related cell death

• Published in: PloS one 2015-01, Vol.10 (1), p.e0116782
• Main Authors: Fan, Jia-Dong, Lei, Pin-Ji, Zheng, Jun-Yi, Wang, Xiang, Li, Shangze, Liu, Huan, He, Yi-Lei, Wang, Zhao-Ning, Wei, Gang, Zhang, Xiaodong, Li, Lian-Yun, Wu, Min
• Format: Article
• Language: English
• Subjects: Analysis; Apoptosis; Apoptosis - drug effects; Autophagy - drug effects; Autophagy-Related Proteins; Azepines - toxicity; Caspase; Cell death; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; DNA methylation; Drug screening; Gene expression; Gene regulation; Genes; HCT116 Cells; Histone-Lysine N-Methyltransferase - antagonists & inhibitors; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones - metabolism; Humans; Medical screening; Membrane Proteins - genetics; Membrane Proteins - metabolism; Methylation - drug effects; Methyltransferase; Microtubule-Associated Proteins - metabolism; Mortality; p53 Protein; Phagocytosis; Protein metabolism; Quinazolines - toxicity; Rapamycin; RNA Interference; RNA, Small Interfering - metabolism; Signaling; Sirolimus - toxicity; Transcription activation; Transcriptome - drug effects; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0116782

Transcription regulation emerged to be one of the key mechanisms in regulating autophagy. Inhibitors of H3K9 methylation activates the expression of LC3B, as well as other autophagy-related genes, and promotes autophagy process. However, the detailed mechanisms of autophagy regulated by nuclear factors remain elusive. In this study, we performed a drug screen of SMYD2-/- cells and discovered that SMYD2 deficiency enhanced the cell death induced by BIX01294, an inhibitor of histone H3K9 methylation. BIX-01294 induces accumulation of LC3 II and autophagy-related cell death, but not caspase-dependent apoptosis. We profiled the global gene expression pattern after treatment with BIX-01294, in comparison with rapamycin. BIX-01294 selectively activates the downstream genes of p53 signaling, such as p21 and DOR, but not PUMA, a typical p53 target gene inducing apoptosis. BIX-01294 also induces other autophagy-related genes, such as ATG4A and ATG9A. SMYD2 is a methyltransferase for p53 and regulates its transcription activity. Its deficiency enhances the BIX-01294-induced autophagy-related cell death through transcriptionally promoting the expression of p53 target genes. Taken together, our data suggest BIX-01294 induces autophagy-related cell death and selectively activates p53 target genes, which is repressed by SMYD2 methyltransferase.